In recent years new oral anticoagulants have been evaluated in the prevention of venous thromboembolism (VTE) after elective hip or knee arthroplasty, atrial fibrillation to prevent ischemic stroke and in the treatment of acute VTE. While two oral anticoagulants, dabigatran and rivaroxaban, have become available for the prevention of VTE in orthopaedic surgery, other indications still are under evaluation or await approval. There are also areas where these novel drugs have not yet been evaluated. These include patients with acute VTE and cancer, pregnant patients with acute VTE and patient with either rheumatic heart valve disease or artificial heart valves. Finally, in acute care settings, where anticoagulant reversibility is critical, such as during and after coronary artery bypass surgery or acute PCI setting in patients with high bleeding risk, novel intravenous anticoagulant drugs with either short half life or specific antidotes may have added value. This article will focus on these unresolved issues.